Estrid Høgdall

Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies

BACKGROUND Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes. METHODS We pooled primary data from 13 population-based case-control studies, including 10,157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13,904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births. RESULTS Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours. CONCLUSIONS We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

PURPOSE The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. PATIENTS AND METHODS The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. RESULTS In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). CONCLUSION These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

Human Papillomavirus Genotyping and p16 Expression As Prognostic Factors for Patients With American Joint Committee on Cancer Stages I to III Carcinoma of the Anal Canal

PURPOSE Carcinomas of the anal canal are strongly associated with the human papillomavirus (HPV). Expression of p16 is used as a surrogate marker of HPV infection. In a retrospective study, we evaluated HPV genotyping and p16 expression as prognostic markers of overall survival (OS) and disease-specific survival (DSS) in patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to III carcinoma of the anal canal. PATIENTS AND METHODS HPV genotyping polymerase chain reaction (high-risk subtypes 16, 18, 31, 33, 45, 52, and 58) and immunohistochemical expression of p16 were analyzed by using paraffin-embedded tumor biopsies from 143 anal carcinomas. The patients were treated with combined chemoradiotherapy or radiotherapy alone. RESULTS HPV16 was detected in 81.0% of the tumors, followed by HPV33 (5.1%), HPV18 (2.2%), and HPV58 (0.7%). p16 positivity was found in 92.9% of the tumors. In univariable survival analysis, HPV positivity was significantly correlated with improved OS (74% v 52%; P=.036) and DSS (84% v 52%; P=.002), and p16 positivity was significantly correlated with improved OS (76% v 30%; P<.001) and DSS (85% v 30%; P<.001). In multivariable COX analysis that included HPV status, p16 status, sex, T stage, N stage, and treatment, p16 positivity remained an independent prognostic factor for OS (hazard ratio [HR], 0.07; 95% CI, 0.01 to 0.61; P=.016) and DSS (HR, 0.07; 95% CI, 0.01 to 0.53; P=.011). CONCLUSION p16 positivity is an independent prognostic factor for OS and DSS in patients with AJCC stages I to III carcinoma of the anal canal.

BRAF inhibition improves tumor recognition by the immune system: Potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer

In spite of the fact that they occur at high rates, the clinical responses of BRAFV600 mutant metastatic melanoma to BRAF inhibitors are usually short-lasting, with most cases progressing within less than 8 mo. Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer, which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma. Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAFV600 mutant melanoma cell lines in vitro. Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8+ T cells. Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins. In conclusion, our preclinical data suggest that an appropriately timed sequential treatment of BRAFV600 mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells.

Does the use of diagnostic PET/CT cause stage migration in patients with primary advanced ovarian cancer?

OBJECTIVE To investigate if the use of diagnostic FDG-PET/CT leads to stage migration in patients with advanced ovarian cancer and to evaluate the prognostic significance of FDG-PET/CT. METHODS From September 2004 to August 2007, 201 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. On 15 August, 2009 overall survival and prognostic variables were analysed in 66 ovarian cancer patients (64 stage III and 2 stage IV). RESULTS Median follow-up was 30.2 months; median age was 62.5 years (range 35-85 years); 97% (64/66) had a performance status <or=2; 38% (25/66) underwent complete debulking (no macroscopic residual tumor); 51% (39/66) was diagnosed with PET/CT stage III and 41% (27/66) was diagnosed with PET/CT stage IV. Survival was significantly longer for patients with PET/CT stage III than for patients with PET/CT stage IV (P=0.03). Using univariate analysis, PET/CT stage III (P=0.03), complete debulking (no macroscopic residual tumor) (P=0.002), and GOG performance status <or=2 (P=0.04) were statistically significant prognostic variables. Using multivariate Cox regression analysis, complete debulking was the only statistically significant independent prognostic variable (P=0.02). CONCLUSION In primary advanced ovarian cancer the use of diagnostic FDG-PET/CT leads to stage migration. Adequate staging is the foundation for ovarian cancer treatment and advanced imaging for optimal evaluation of metastases should be promoted in clinical trials. The strongest determinant of patient outcome is residual abdominal tumor after primary surgery.

Standardized FDG uptake as a prognostic variable and as a predictor of incomplete cytoreduction in primary advanced ovarian cancer

Abstract Introduction. In patients with advanced ovarian cancer undergoing preoperative PET/CT, we investigated the prognostic value of SUV in the primary tumor and we evaluated the value of SUV for predicting incomplete primary cytoreduction (macroscopic residual tumor). Material and methods. From September 2004 to August 2007, 201 consecutive patients with a pelvic tumor and a Risk of Malignancy Index (RMI) > 150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within two weeks prior to standard surgery/debulking of a pelvic tumor. At two-year follow-up (August 15, 2009) the association between SUV and overall survival/cytoreductive result were analyzed in 60 ovarian cancer patients (58 stage III and two stage IV). Results. At inclusion median age was 62 years (range 35–85 years); 97% (58/60) had a performance status ≤2; 42% (25/60) underwent complete debulking (no macroscopic residual tumor); median SUVmax was 13.5 (range 2.5–39.0). Median follow-up was 30.2 months. At follow-up 57% (34/60) were alive and 43% (26/60) had died from ovarian cancer. SUVmax in patients alive was not statistically different from SUVmax in dead patients (p=0.69), and SUVmax was not correlated with the amount of residual tumor after surgery (p=0.19). Using univariate Cox regression analysis, residual tumor was a significant prognostic variable (p=0.001); SUVmax was not a statistically significant prognostic variable (p=0.86). Discussion. FDG uptake (SUVmax) in the primary tumor of patients with advanced ovarian cancer was not a prognostic variable and the FDG uptake did not predict complete cytoreduction after primary surgery. Future prospective clinical trials will need to clarify if other PET tracers can serve as prognostic variables in ovarian cancer.

CT versus FDG‐PET/CT response evaluation in patients with metastatic colorectal cancer treated with irinotecan and cetuximab

We compared morphologic computed tomography (CT)‐based to metabolic fluoro‐deoxy‐glucose (FDG) positron emission tomography (PET)/CT‐based response evaluation in patients with metastatic colorectal cancer and correlated the findings with survival and KRAS status. From 2006 to 2009, patients were included in a phase II trial and treated with cetuximab and irinotecan every second week. They underwent FDG‐PET/CT examination at baseline and after every fourth treatment cycle. Response evaluation was performed prospectively according to Response Evaluation Criteria in Solid Tumors (RECIST 1.0) and retrospectively according to Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Best overall responses were registered. Sixty‐one patients were eligible for response evaluation. Partial response (PR) rate was 18%, stable disease (SD) rate 64%, and progressive disease (PD) rate 18%. Partial metabolic response (PMR) rate was 56%, stable metabolic disease rate 33%, and progressive metabolic disease (PMD) rate 11%. Response agreement was poor, κ‐coefficient 0.19. Hazard ratio for overall survival for responders (PR/PMR) versus nonresponders (PD/PMD) was higher for CT‐ than for FDG‐PET/CT evaluation. Within patients with KRAS mutations, none had PR but 44% had PMR. In conclusion, morphologic and metabolic response agreement was poor primarily because a large part of the patients shifted from SD with CT evaluation to PMR when evaluated with FDG‐PET/CT. Furthermore, a larger fraction of the patients with KRAS mutations had a metabolic treatment response.

HPV genotype distribution in older Danish women undergoing surgery due to cervical cancer

The prevalence of human papillomavirus (HPV)16/18 in cervical cancer may decrease with age. This study aimed to describe the HPV genotype distribution in Danish women aged 55 years or older with cervical cancer.

The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies

PURPOSE Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. METHODS From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. RESULTS Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. CONCLUSION Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.

Serum YKL-40 and gestational diabetes - an observational cohort study.

To examine serum YKL‐40 in women developing gestational diabetes mellitus (GDM). In the present large observational cohort study of 1179 pregnant women, we determined serum YKL‐40 four times during pregnancy (at gestational age 12, 20, 25, and 32 weeks). Pregnancy outcome was obtained from medical records. Sixty‐eight women (5.8%) developed GDM. Serum YKL‐40 increased from gestational age (GA) 12 weeks and the following weeks in the women who developed GDM and was independent of BMI, parity, and maternal age (OR = 2.69, 95% CI: 1.45–5.00, p = 0.002). No association was found between serum YKL‐40 and the oral glucose tolerance test results. In conclusion, YKL‐40 significantly increased in pregnant women with GDM compared with women without GDM, probably reflecting the low‐grade inflammation of GDM. However, we did not find an association between serum concentrations of YKL‐40 in early pregnancy and the development of GDM and thus we conclude that YKL‐40 alone is not usable as a biomarker for early prediction of GDM.